1. Field of the Invention
The present invention relates to a class of imidazolopyridines compounds capable of binding to the active site of a serine/threonine kinase, and which can be used to treat conditions involving the degradation of extra-cellular matrix (ECM), such as joint degeneration and diseases involving such degradation and/or inflammation.
2. Description of the Related Art
Diseases involving the degradation of extra-cellular matrix include, but are not limited to, psoriatic arthritis, juvenile arthritis, early arthritis, reactive arthritis, osteoarthritis, ankylosing spondylitis, osteoporosis, musculoskeletal diseases like tendonitis and periodontal disease, cancer metastasis, airway diseases (COPD, asthma), renal and liver fibrosis, cardio-vascular diseases like atherosclerosis and heart failure, and neurological diseases like neuroinflammation and multiple sclerosis. Diseases involving primarily joint degeneration include, but are not limited to, psoriatic arthritis, juvenile arthritis, early arthritis, reactive arthritis, osteoarthritis, and ankylosing spondylitis.
Rheumatoid arthritis (RA) is a chronic joint degenerative disease, characterized by inflammation and destruction of the joint structures. When the disease is unchecked, it leads to substantial disability and pain due to loss of joint functionality and even premature death. The aim of an RA therapy, therefore, is not to slow down the disease but to attain remission in order to stop the joint destruction. Besides the severity of the disease outcome, the high prevalence of RA (˜0.8% of adults are affected worldwide) means a high socio-economic impact. (For reviews on RA, we refer to Smolen and Steiner (2003); Lee and Weinblatt (2001); Choy and Panayi (2001); O'Dell (2004) and Firestein (2003)).
It is widely accepted that RA is an auto-immune disease, the initial trigger(s) does mediate, in a predisposed host, a cascade of events that leads to the activation of various cell types (B-cells, T-cells, macrophages, fibroblasts, endothelial cells, dendritic cells and others). Concomitantly, an increased production of various cytokines is observed in the joints and tissues surrounding the joint (e.g. TNF-α, IL-6, IL-1, IL-15, IL-18 and others). As the disease progresses, the cellular activation and cytokine production cascade becomes self-perpetuating. At this early stage, the destruction of joint structures is already very clear. Thirty percent of the patients have radiographic evidence of bone erosions at the time of diagnosis and this proportion increases to 60 percent after two years.
Histological analysis of the joints of RA patients clearly evidences the mechanisms involved in the RA-associated degradative processes (FIG. 1). This analysis shows that the main effector responsible for RA-associated joint degradation is the pannus; whereas the synovial fibroblast (SF), by producing diverse proteolytic enzymes, is the prime driver of cartilage and bone erosion. A joint classically contains two adjacent bones that articulate on a cartilage layer, surrounded by the synovial membrane and joint capsule. In the advanced RA patient, the synovium of the joint increases in size to form the pannus, due to the proliferation of the synovial fibroblasts and the infiltration of mononuclear cells such as T-cells, B-cells, monocytes, macrophages and neutrophils. The pannus mediates the degradation of the adjacent cartilage, leading to the narrowing of the joint space, and has the potential to invade adjacent bone and cartilage. As bone and cartilage tissues are composed mainly of collagen type I or II, respectively, the pannus destructive and invasive properties are mediated by the secretion of collagenolytic proteases, principally the matrix metalloproteinases (MMPs). The erosion of the bone under and adjacent to the cartilage is also part of the RA process, and results principally from the presence of osteoclasts at the interface of bone and pannus. Osteoclasts are multinucleated cells that, upon adhesion to the bone tissue, form a closed compartment, within which the osteoclasts secrete proteases (cathepsin K, MMP9) that degrade the bone tissue. The osteoclast population in the joint is abnormally increased by osteoclast formation from precursor cells induced by the secretion of the receptor activator of NFκB ligand (RANKL) by activated SFs and T-cells.
Various collagen types have a key role in defining the stability of the extracellular matrix (ECM). Collagen type I and collagen type II, for example, are the main components of bone and cartilage, respectively. Collagen proteins typically organize into multimeric structures referred to as collagen fibrils. Native collagen fibrils are very resistant to proteolytic cleavage. Only a few types of ECM-degrading proteins have been reported to have the capacity to degrade native collagen: MMPs and cathepsins. Among the cathepsins, cathepsin K, which is active mainly in osteoclasts, is the best characterized. Among the MMPs, MMP1, MMP2, MMP8, MMP13 and MMP14 are known to have collagenolytic properties. The correlation between an increased expression of MMP1 by SFs and the progression of the arthritic disease is well-established and is predictive for joint erosive processes (Cunnane et al., 2001). In the context of RA, therefore, MMP1 represents a highly relevant collagen degrading protein. In vitro, the treatment of cultured SFs with cytokines relevant in the RA pathology (e.g. TNF-α and IL1β) will increase the expression of MMP1 by these cells (Andreakos et al., 2003). Monitoring the levels of MMP1 expressed by SFs therefore is a relevant readout in the field of RA as it is indicative for the activation of SFs towards an erosive phenotype that, in vivo, is responsible for cartilage degradation. Inhibition of the MMP1 expression by SFs represents a valuable therapeutic approach towards the treatment of RA.
The activity of the ECM-degrading proteins can also be causative or correlate with the progression of various diseases different from RA, as e.g. other diseases that involve the degradation of the joints. These diseases include, but are not limited to, psoriatic arthritis, juvenile arthritis, early arthritis, reactive arthritis, osteoarthritis, and ankylosing spondylitis. Other diseases that may be treatable with compounds identified according to the present invention and using the targets involved in the expression of MMPs as described herein are osteoporosis, musculoskeletal diseases like tendonitis and periodontal disease (Gapski et al., 2004), cancer metastasis (Coussens et al., 2002), airway diseases (COPD, asthma) (Suzuki et al., 2004), lung, renal fibrosis (Schanstra et al., 2002), liver fibrosis associated with chronic hepatitis C (Reif et al., 2005), cardio-vascular diseases like atherosclerosis and heart failure (Creemers et al., 2001), and neurological diseases like neuroinflammation and multiple sclerosis (Rosenberg, 2002). Patients suffering from such diseases may benefit from stabilizing the ECM (by protecting it from degradation).
Transforming growth factor-β activated kinase 1 (TAK1), is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, originally identified as a key regulator of MAP kinase activation in TGFβ/BMP signaling (Yamaguchi et al. 1995; Shibuya et al. 1998). Later studies have reported that Drosophila TAK1 is required for both c-jun N-terminal kinase and NFκB activation in response to immune challenge by gram-negative bacteria infection (Vidal et al., 2001; Boutros et al., 2002). By now, TAK1 has also been shown to function as a critical upstream molecule of NFκB and MAPK signaling in various mammalian cell types after stimulation with IL1, TNF and lipopolysaccharide, which activates Toll-like receptor (TLR) signaling (Ninomiya-Tsuji et al., 1999; Sakurai et al., 1999; Irie et al., 2000; Blonska et al., 2005; Shim et al., 2005; Dong et al., 2006). In addition, TAK1 was shown to be required for RANKL induced osteoclast differentiation (Mizukami et al., 2002; Huang et al., 2006). In these signaling cascades, TAK1 is recruited to TRAF6 complexes in response to IL1R, TLR and RANKL signaling or to TRAF2 complexes in response to TNFR stimulation. Activated TAK1 phosphorylates MAPK kinases (MAP2K) MKK4 and MKK3/6, which in turn can activate JNK and p38 mitogen-activated protein kinase, leading to the activation of the activator protein 1 (AP1) transcription factor. Furthermore, TAK1 activates IκB kinase (IKK) signaling pathway, leading to the nuclear translocation of NFκB. Furthermore, studies with mice having B-cell specific or T-cell specific TAK1 deficiencies revealed that TAK1 was indispensable for cellular responses to B cell receptor cross-linking and T cell development, survival and function (Sato et al., 2005; Wan et al., 2006). It has also recently been shown that siRNA-mediated knock-down of TAK1 in the human SW1353 chondrosarcoma cell line significantly reduced IL1 triggered expression of MMP1 and MMP13, enzymes involved in ECM degradation in arthritis (Klatt et al. 2006). Taken together, these findings suggest critical roles for TAK1 in inflammatory and immunological responses.
Since TAK1 is a key molecule in pro-inflammatory signaling pathways, TAK1 inhibition can be expected to be effective in diseases associated with inflammation and tissue destruction such as rheumatoid arthritis. With respect to the latter, it has recently been shown that siRNA-mediated knock-down of TAK1 in the human SW1353 chondrosarcoma cell line significantly reduced IL1 triggered expression of MMP1 and MMP13, enzymes involved in ECM degradation in arthritis (Klatt et al. 2006).
The current therapies for RA are not satisfactory due to a limited efficacy (no adequate therapy exists for 30% of the patients). This calls for additional strategies to achieve remission. Remission is required since residual disease bears the risk of progressive joint damage and thus progressive disability. Inhibiting the immuno-inflammatory component of the RA disease, which represents the main target of drugs currently used for RA treatment, does not result in a blockade of joint degradation, the major hallmark of the disease.
Accordingly, a need exists for the identification of new agents that can more effectively and reliably treat conditions such as RA, and it is in response to this need and toward its satisfaction, that the present invention is directed.